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Öğe Alanine scanning effects on the biochemical and viophysical properties of intrinsically disordered proteins: a case study of the histidine to alanine mutations in amyloid-beta(42)(Amer Chemical Soc, 2019) Weber, Orkide Coşkuner; Uversky, Vladimir N.Alanine scanning is a tool in molecular biology that is commonly used to evaluate the contribution of a specific amino acid residue to the stability and function of a protein. Additionally, this tool is also used to understand whether the side chain of a specific amino acid residue plays a role in the protein's bioactivity. Furthermore, computational alanine scanning methods are utilized to predict the thermodynamic properties of proteins. These studies are utilized with the assumption that the biochemical and biophysical properties of a protein do not change with alanine scanning. Our study was dedicated to analyze the effect of alanine scanning on the biochemical and biophysical properties of intrinsically disordered proteins. To this end, we studied the impact of widely used histidine to alanine mutations in amyloid-beta (A beta). We found that the secondary and tertiary contacts, salt bridge formations, and thermodynamic properties, as well as disorder propensities and aggregation predisposition of A beta, are impacted by the single and triple point histidine to alanine mutations. Experimental and computational studies employing the alanine scanning technique for mutating histidine to alanine in the analysis of intrinsically disordered proteins have to consider these effects.Öğe BMP-2 and BMP-9 binding specificities with ALK-3 in aqueous solution with dynamics(Elsevier Science Inc, 2017) Weber, Orkide Coşkuner; Uversky, Vladimir N.Signal ligands of the transforming growth factor-beta (TGF-beta) superfamily include the bone morphogenetic proteins (BMPs). BMPs bind to type I and type II serine-threonine kinase receptors and trigger the transphosphorylation cascade, wherein the active type II receptor phosphorylates the inactive type I receptor. This process further activates the cytoplasmic effectors of the pathway, such as SMAD proteins, which are homologs of both the Drosophila protein MAD (mothers against decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size). Even though biological and medicinal studies have been performed on these complex species, we currently do not know the underlying molecular mechanisms of the signal ligand interactions with the receptors. Detailed understanding of these interactions increases our knowledge about these proteins, and also can provide the lacking information for successful mutation experiments. This study focuses on the computational analysis of binding affinities and structural binding specificities of two different types of BMPs (BMP-2 and BMP-9) to the activin receptor-. like kinases (ALK-3) in solution. For studying the binding characteristics of BMP-2 or BMP-9 with ALK-3 in aqueous solution, we performed extensive molecular dynamics simulations coupled with thermodynamic calculations. The calculated thermodynamic properties show that the BMP-2/ALK-3 complex is thermodynamically more stable than a possible BMP-9/ALK-3 species in aqueous solution. The binding free energies indicate that ALK-3 preferably binds to BMP-2 instead of BMP-9. The structural analysis shows that ALK-3 binding with BMP-2 occurs in a perfectly symmetry pathway, whereas this symmetry is lost for possible ALK-3 interactions with BMP-9. The Phe49 to Va170 loop region of BMP-2 presents strong inter-molecular interactions with ALK-3. On the other hand, BMP-9 presents weaker interactions with ALK-3 via a non-continuous sequence. ALK-3-binding region of BMP-2 corresponds to the region predicted to be flexible by our intrinsic disorder analysis, whereas the related region of BMP-9 is expected to be noticeably less flexible. This study proposes that mutating the BMP-9 with the partial Phe49 to Va170 sequence of BMP-2 can help to increase the reactivity of BMP-9 towards stable ALK-3 binding, which in turn has the potential to develop new signaling pathways for improving the formation of tissues and to prevent or treat severe diseases. Furthermore, this study also demonstrates the usefulness of theoretical physical chemistry tools, such as molecular dynamics simulations and the ProtMet simulation software package in the structural characterization of the TGF-beta superfamily proteins. (C) 2017 Elsevier Inc. All rights reserved.Öğe Challenges and limitations in the studies of glycoproteins: A computational chemist's perspective(WILEY, 2021) Ballı, Öykü İrem; Uversky, Vladimir N.; Durdağı, Serdar; Weber, Orkide CoşkunerExperimenters face challenges and limitations while analyzing glycoproteins due to their high flexibility, stereochemistry, anisotropic effects, and hydration phenomena. Computational studies complement experiments and have been used in characterization of the structural properties of glycoproteins. However, recent investigations revealed that computational studies face significant challenges as well. Here, we introduce and discuss some of these challenges and weaknesses in the investigations of glycoproteins. We also present requirements of future developments in computational biochemistry and computational biology areas that could be necessary for providing more accurate structural property analyses of glycoproteins using computational tools. Further theoretical strategies that need to be and can be developed are discussed herein.Öğe Current challenges and limitations in the studies of intrinsically disordered proteins in neurodegenerative diseases by computer simulations(Bentham Science Publishers, 2020) Akbayrak, İbrahim Yağız; Çağlayan, Şule İrem; Özcan, Zilan; Uversky, Vladimir; Weber, Orkide CoşkunerExperiments face challenges in the analysis of intrinsically disordered proteins in solution due to fast conformational changes and enhanced aggregation propensity. Computational studies complement experiments, being widely used in the analyses of intrinsically disordered proteins, especially those positioned at the centers of neurodegenerative diseases. However, recent investigations – including our own – revealed that computer simulations face significant challenges and limitations themselves. In this review, we introduced and discussed some of the scientific challenges and limitations of computational studies conducted on intrinsically disordered proteins. We also outlined the importance of future developments in the areas of computational chemistry and computational physics that would be needed for generating more accurate data for intrinsically disordered proteins from computer simulations. Additional theoretical strategies that can be developed are discussed herein. © 2020 Bentham Science Publishers.Öğe Epitope region identification challenges of intrinsically disordered proteins in neurodegenerative diseases: Secondary structure dependence of alpha-synuclein on simulation techniques and force field parameters(Wiley, 2020) Mandacı, Sunay Yağız; Çalışkan, Murat; Sarıaslan, M. Furkan; Uversky, Vladimir N.; Weber, Orkide CoşkunerDue to fast aggregation processes of many disordered proteins in neurodegenerative diseases, it is difficult to study their epitope regions at the monomeric and oligomeric levels. Computer simulations complement experiments and have been used to identify the epitope regions of proteins. Residues that adopt beta-sheet conformation play a central role in the oligomerization and aggregation mechanisms of such proteins, including alpha-synuclein, which is at the center of Parkinson's and Alzheimer's diseases. In this study, we simulated the monomeric alpha-synuclein protein in an aqueous environment to evaluate its secondary structure properties, including beta-sheet propensity, and radius of gyration by replica exchange molecular dynamics simulations. We also obtained the molecular dynamics simulation trajectories of alpha-synuclein that were conducted using various force field parameters by the David E. Shaw group. Using these trajectories, we calculated the impacts of force field parameters on alpha-synuclein secondary structure properties and radius of gyration values and obtained results are compared with our data from REMD simulations. This study shows that the chosen force field parameters and computer simulation techniques effect the predicted secondary structure properties and radius of gyration values of alpha-synuclein in water. Herewith, we illustrate the challenges in epitope region identification of intrinsically disordered proteins in neurodegenerative diseases by current computer simulations.Öğe Insights into the molecular mechanisms of Alzheimer's and Parkinson's diseases with molecular simulations: understanding the roles of artificial and pathological missense mutations in intrinsically disordered proteins related to pathology(Mdpi, 2018) Weber, Orkide Coşkuner; Uversky, Vladimir N.Amyloid-beta and alpha-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer's and Parkinson's disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid- and -synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer's and Parkinson's diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid- and -synuclein in relation to the pathologies of Alzheimer's and Parkinson's diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer's and Parkinson's diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid- and -synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid- and -synuclein, such as -structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer's and Parkinson's diseases. This information represents an important foundation for the successful and efficient drug design studies.Öğe Intrinsically disordered proteins in various hypotheses on the pathogenesis of Alzheimer's and Parkinson's diseases(Elsevier Academic Press Inc, 2019) Weber, Orkide Coşkuner; Uversky, Vladimir N.Amyloid-beta (A beta) and alpha-synuclein (alpha S) are two intrinsically disordered proteins (IDPs) at the centers of the pathogenesis of Alzheimer's and Parkinson's diseases, respectively. Different hypotheses have been proposed for explanation of the molecular mechanisms of the pathogenesis of these two diseases, with these two IDPs being involved in many of these hypotheses. Currently, we do not know, which of these hypothesis is more accurate. Experiments face challenges due to the rapid conformational changes, fast aggregation processes, solvent and paramagnetic effects in studying these two IDPs in detail. Furthermore, pathological modifications impact their structures and energetics. Theoretical studies using computational chemistry and computational biology have been utilized to understand the structures and energetics of A beta and alpha S. In this chapter, we introduce A beta and alpha S in light of various hypotheses, and discuss different experimental and theoretical techniques that are used to study these two proteins along with their weaknesses and strengths. We suggest that a promising solution for studying A beta and alpha S at the center of varying hypotheses could be provided by developing new techniques that link quantum mechanics, statistical mechanics, thermodynamics, bioinformatics to machine learning. Such new developments could also lead to development in experimental techniques.Öğe Molecular simulations of IDPs: From ensemble generation to IDP interactions leading to disorder-to-order transitions(Academic Press Inc Elsevier Science, 2021) Fatafta, Hebah; Samantray, Suman; Sayyed-Ahmad, Abdallah; Weber, Orkide Coşkuner; Strodel, Birgit; N. Uversky, VladimirIntrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure but do exhibit some dynamical and structural ordering. The structural plasticity of IDPs indicates that entropy-driven motions are crucial for their function. Many IDPs undergo function-related disorder-to-order transitions upon by their interaction with specific binding partners. Approaches that are based on both experimental and theoretical tools enable the biophysical characterization of IDPs. Molecular simulations provide insights into IDP structural ensembles and disorder-to-order transition mechanisms. However, such studies depend strongly on the chosen force field parameters and simulation techniques. In this chapter, we provide an overview of IDP characteristics, review all-atom force fields recently developed for IDPs, and present molecular dynamics-based simulation methods that allow IDP ensemble generation as well as the characterization of disorder-to-order transitions. In particular, we introduce meta-dynamics, replica exchange molecular dynamics simulations, and also kinetic models resulting from Markov State modeling, and provide various examples for the successful application of these simulation methods to IDPs.Öğe Revisiting cu(II) bound amyloid-?40 and amyloid-?42 peptides: varying coordination chemistries(Turkish Chemical Society, 2018) Weber, Orkide CoşkunerMetal ions and intrinsically disordered peptides amyloid-?40 and amyloid-?42 are at the center of Alzheimer´s disease pathology. Divalent copper ion binds to amyloid-?40 and amyloid-?42 peptides with varying coordination chemistries. Experiments face challenges in the measurements of divalent copper ion bound monomeric amyloid-?40 and amyloid-?42 in an aqueous solution medium because of fast conformational changes, rapid aggregation processes and solvent effects. Theoretical studies complement experiments and provide insights at the atomic and molecular levels with dynamics. However, until recently, potential functions for simulating divalent copper ion bound amyloid-?40 and amyloid-?42 peptides with varying coordination chemistries were lacking. Using new potential functions that were developed for divalent copper centers, Cu(II), including three histidine residues and an oxygen-ligated amino acid residue, the structures and thermodynamic properties of Cu(II)-bound amyloid-?40 and amyloid-?42 peptides in an aqueous solution medium were studied. For these purposes, extensive first principles calculations and replica exchange molecular dynamics simulations were conducted. In this study, the secondary and tertiary structural properties, conformational Gibbs free energy values, potential of mean force surfaces, salt bridges and aggregation propensities of aqueous Cu(II)-bound amyloid-?40 and amyloid-?42 peptides are presented. Different than previous findings in the literature, results clearly show that the coordination chemistry variations impact the structural and thermodynamic properties of divalent Cu(II) bound amyloid-? alloforms in water. Specificities about these differences are revealed in this study at the atomic level with dynamics. Results presented herein are the first to offer a comparison of the monomeric Cu(II)-bound amyloid-?40 and amyloid-?42 peptides with varying coordination chemistries using bonded model potential functions. © 2018, Turkish Chemical Society. All rights reserved.Öğe Secondary structure dependence of amyloid-beta(1-40) on simulation techniques and force field parameters(Wiley, 2021) Çalışkan, Murat; Mandacı, Sunay Y.; Uversky, Vladimir N.; Weber, Orkide CoşkunerOur recent studies revealed that none of the selected widely used force field parameters and molecular dynamics simulation techniques yield structural properties for the intrinsically disordered alpha-synuclein that are in agreement with various experiments via testing different force field parameters. Here, we extend our studies on the secondary structure properties of the disordered amyloid-beta(1-40) peptide in aqueous solution. For these purposes, we conducted extensive replica exchange molecular dynamics simulations and obtained extensive molecular dynamics simulation trajectories from David E. Shaw group. Specifically, these molecular dynamics simulations were conducted using various force field parameters and obtained results are compared to our replica exchange molecular dynamics simulations and experiments. In this study, we calculated the secondary structure abundances and radius of gyration values for amyloid-beta(1-40) that were simulated using varying force field parameter sets and different simulation techniques. In addition, the intrinsic disorder propensity, as well as sequence-based secondary structure predisposition of amyloid-beta(1-40) and compared the findings with the results obtained from molecular simulations using various force field parameters and different simulation techniques. Our studies clearly show that the epitope region identification of amyloid-beta(1-40) depends on the chosen simulation technique and chosen force field parameters. Based on comparison with experiments, we find that best computational results in agreement with experiments are obtained using the a99sb*-ildn, charmm36m, and a99sb-disp parameters for the amyloid-beta(1-40) peptide in molecular dynamics simulations without parallel tempering or via replica exchange molecular dynamics simulations.Öğe Structures of the Wild-Type and S59L Mutant CHCHD10 ProteinsImportant in Amyotrophic Lateral Sclerosis-FrontotemporalDementia(American Chemical Society, 2022) Alıcı, Hakan; Uversky, Vladimir N.; Kang, David E.; Woo, Junga Alexa; Weber, Orkide CoşkunerThe S59L genetic mutation of the mitochondrial coiled-coil-helix-coiled-coil-helixdomain-containing protein 10 (CHCHD10) is involved in the pathogenesis of amyotrophic lateralsclerosis (ALS) and frontotemporal dementia (FTD). The wild-type and mutant forms of this proteincontain intrinsically disordered regions, and their structural characterization has been facing challenges.Here, for thefirst time in the literature, we present the structural ensemble properties of the wild-type andS59L mutant form of CHCHD10 in an aqueous solution environment at the atomic level with dynamics.Even though available experiments suggested that the S59L mutation may not change the structure of theCHCHD10 protein, our structural analysis clearly shows that the structure of this protein is significantlyaffected by the S59L mutation. We present here the secondary structure components with theirabundances per residue, the tertiary structure properties, the free energy surfaces based on the radius ofgyration and end-to-end distance values, the Ramachandran plots, the quantity of intramolecularhydrogen bonds, and the principal component analysis results. These results may be crucial in designingmore efficient treatment for ALS and FTD diseases.Öğe Transition metal Ion interactions with disordered Amyloid-beta Peptides in the pathogenesis of Alzheimer's disease: insights from computational chemistry studies(Amer Chemical Soc, 2019) Strodel, Birgit; Weber, Orkide CoşkunerMonomers and oligomers of the amyloid-beta peptide aggregate to form the fibrils found in the brains of Alzheimer's disease patients. These monomers and oligomers are largely disordered and can interact with transition metal ions, affecting the mechanism and kinetics of amyloid-beta aggregation. Due to the disordered nature of amyloid-beta, its rapid aggregation, as well as solvent and paramagnetic effects, experimental studies face challenges in the characterization of transition metal ions bound to amyloid-beta monomers and oligomers. The details of the coordination chemistry between transition metals and amyloid-beta obtained from experiments remain debated. Furthermore, the impact of transition metal ion binding on the monomeric or oligomeric amyloid-beta structures and dynamics are still poorly understood. Computational chemistry studies can serve as an important complement to experimental studies and can provide additional knowledge on the binding between amyloid-beta and transition metal ions. Many research groups conducted first-principles calculations, ab initio molecular dynamics simulations, quantum mechanics/classical mechanics simulations, and classical molecular dynamics simulations for studying the interplay between transition metal ions and amyloid-beta monomers and oligomers. This review summarizes the current understanding of transition metal interactions with amyloid-beta obtained from computational chemistry studies. We also emphasize the current view of the coordination chemistry between transition metal ions and amyloid-beta. This information represents an important foundation for future metal ion chelator and drug design studies aiming to combat Alzheimer's disease.Öğe Tyrosine regulates beta-sheet structure formation in amyloid-beta(42): a new clustering algorithm for disordered proteins(Amer Chemical Soc, 2017) Weber, Orkide Coşkuner; Uversky, Vladimir N.Our recent studies show that the single Tyr residue in the sequence of amyloid-beta(42) (A beta(42)) is reactive toward various ligands, including metals and adenosine trisphospate (see: Coskuner, O. J. Biol. Inorg. Chem. 2016 21, 957-973 and Coskuner, O.; Murray, I. V. J. J. Alzheimer's Dis. 2014 41, 561-574). However, the exact role of Tyr in the structures of A(beta 42) remains unknown. To fill this gap, here we analyzed the role of Tyr and the impact of the TyrlOAla mutation on the structural ensemble of A beta(42). beta-Sheet formation in the structural ensemble of A beta(42) is directly associated with the reactivity of this peptide toward ligand-receptor interactions, including self-assembly. On the basis of our findings, Tyr plays a crucial role in beta-sheet emergence in the structures of A beta(42), and the TyrlOAla mutation greatly suppresses or diminishes beta-sheet formation in the overall structures of monomeric A beta(42). A new strategy for predicting the degree of stability and an "order in disorder" algorithm using secondary structure properties and thermodynamics were developed and applied for the Tyr10Ala mutant and wild-type A beta(42) analysis. This new clustering algorithm may help in selecting disordered protein structure ensembles for drug design studies. TyrlOAla mutation results in less stable and less compact structures, a conclusion based on our varying thermodynamic studies using harmonic and quasi-harmonic methods. Furthermore, the use of various intrinsic disorder predictors suggests that the TyrlOAla mutation impacts the A beta(42) propensity for disorder, whereas the application of several computational tools for aggregation prediction suggests that this mutation decreases the A beta(42) aggregation propensity. The mid-domain interactions with the N- and C-terminal regions weaken or disappear upon TyrlOAla mutation. In addition, the N- and C-terminal interactions are weaker or diminished upon the introduction of the TyrlOAla mutation to the structures of the A beta(42) peptide in solution.
